International patent application no. WO 88/00050 describes the antiretroviral and anti-HBV activity of a series of 3′-fluorinated nucleosides, including the compounds 2′,3′-dideoxy, 3′-fluoroguanosine (FLG) and 3′-fluorothymidine (FLT). The latter compound underwent clinical evaluation as an anti-HIV agent and although its antiviral activity and pharmacokinetics were good, it showed unexpected toxicity (Flexner et al, J Inf Dis 170(6) 1394–403 (1994)). The former compound FLG is very active in vitro however the present inventors have detected that its bioavailability is so poor—around 4%—that the in vivo utility of the compound has thus far been limited to intraperitoneally or subcutaneously administered animal models.
U.S. Pat. No. 4,963,662 discloses generically a series of 3′-fluorinated nucleosides and corresponding triphosphates and specifically describes the preparation of the 5′-Opalmitoyl derivative of FLT, without reporting any improvement in bioavailability. International patent application WO 93 13778 describes FLG derivatives modified at the 6-position of the base, in particular with n-propoxy, cyclobutoxy, cyclopropanylamino, piperidino or pyrrolidino. International patent application no. 93 14103 describes FLG derivatives where the oxygen at the guanine 6-position is replaced with amino, ether, halo or sulphonate.